In the Beginning, Before There Was RNA, There Was...TNA?

Where did life come from? There are two kinds of answers to the question. One looks at the construction of organisms and says that all of the components of the organism from its DNA to its body parts were designed with the end goal, the organism, in mind. The other answer looks at the construction of an organism, and says that all of the parts and pieces came first and through selection pressure and trial and error, a functioning organism emerged.

The first answer builds the organism from the top down with its overall design in mind from the start, while the second answer builds the organism from the bottom up.

Origin-of-life research is predominantly of the bottom-up variety, with the RNA-world scenario being the favorite origins theory among scientists at the moment. If you were to break an organism down to its component parts, you'd find that organisms are composed of genetic material. The difficulty in determining the origin this material, such as RNA and DNA, is that RNA and DNA are needed to make proteins and proteins are needed to make DNA and RNA. Therefore the first genetic material must have been made by a completely different process.

Enter the ribozyme, an RNA molecule that behaves like an enzyme (proteins). The function of ribozymes has given a glimmer of hope that perhaps RNA, rather than DNA, came first. However the ribozyme has limited functionality and does not solve many of the problems that go along with the RNA-world scenario.

The most pressing such problem is the relative chemical instability of RNA molecules. Unlike DNA, whose chemical bases are paired and securely tucked into the interior of a helical structure while the chemically robust ribose phosphates remain exposed on the surface, RNA is single-stranded with the bases exposed to the environment. RNA does have three-dimensional structures that provide some chemical stability, but it is still too delicate for most early-Earth environment models.

True to their own evolutionary thinking, some scientists have speculated that there was a precursor to the RNA molecule, a chemical transitional species, if you will. Ideally, this molecule would have been simpler than the RNA molecule, and therefore easier to synthesize in an early-Earth environment. Yet it would have many of the characteristics of genetic material, such as nucleotide base pairing and a three-dimensional structure with functional activity. Yu et al. report in an article in Nature that threose nucleic acid (TNA) is a viable contender as a pre-RNA transitional molecule.

TNA molecular structure. The TNA backbone is composed of a threose sugar (4 carbon), while DNA and RNA has a ribose sugar (5 carbon). The molecular picture is available here. In TNA, the phosphate groups are bound to the 2 and 3 positions rather than the 3 and 5 positions as in DNA and RNA.

TNA is considered a simpler molecule because it has one fewer carbon, and could theoretically form from two 2-carbon segments. However it is highly speculative to call that an "easier" synthesis than the formation of a ribose sugar. It would likely occur through an aldehyde reaction, similar to the typical ribose synthesis. Since the purine and pyrimidine nucleotide bases would remain the same, the same chemical problems are present. Amines are highly reactive and the synthesis of sugars generally requires an environment that would be prohibitive for nucleotide production. (See Signature in the Cell by Stephen C. Meyer, pp, 301-304, for an excellent explanation of the problems with RNA world chemistry).

The authors had trouble working with polymerases that convert DNA to a TNA library in places where multiple guanine nucleotides were present. They therefore removed GGG strands in DNA, in an effort to avoid stalling the process:

Although the L2 library generates TNA polymers that lack cytidine, we reasoned that this was not a significant concern as cytidine may not have been present in the first genetic material due to its tendency to undergo spontaneous deamination...Furthermore, it has been shown that ribozymes missing cytidine can be generated by in vitro evolution, demonstrating that a three-letter genetic alphabet can still retain the ability to fold and function.

Additionally, inorganic phosphate needs to react (usually with alkyl alcohols) to form a phosphate ester, which is not necessarily any more or less difficult with threose as opposed to ribose. So switching from a 5-carbon sugar to a 4-carbon sugar does not remove many of the chemistry barriers to the RNA world hypothesis.

TNA tertiary structure. TNA does make a helical-type structure, and it can form tertiary structures with functional activity. Its bases can base-pair with itself or with another RNA molecule, allowing for possible information transfer between different genetic systems.

TNA activity. TNA can interact with a few of the same proteins that interact with DNA. Using molecular evolution technology, where possible functional segments of TNA are selected from a random set of synthesized TNA segments, the authors found a few segments that, indeed, demonstrated functional specificity:

The fact that TNA does not appear to be limited in this regard suggests that it may be possible to isolate novel TNA enzymes from pools of random sequencing using in vitro evolution. We suggest that selections of this type could be used to further examine the fitness of TNA as an RNA progenitor in a hypothetical TNA world.

Cut to the chase: Is TNA a precursor to RNA? Unfortunately, there is no way to know.

This experiment assumes the very thing it is trying to prove. The scientists here are assuming that an RNA-first world must have occurred, but there are prohibitive problems with this model, so they select one problem, the complexity and instability of RNA, and seek a solution by finding a simpler molecule that has many similar properties.

TNA is an interesting molecule in and of itself, but there is no indication of how it fits into the grand scheme of an origin-of-life scenario, and there is no way to know if it actually was present in the early Earth (or even in nature) or if it is just an interesting laboratory synthesis.

Some questions that remain to be answered: How would TNA be synthesized in an early-Earth environment? Heat vents, ice crystals, concentrated pools, magma, in an oxidizing or a reducing environment? Is TNA more stable than RNA? If so, is it stable enough not to decompose under harsh environmental conditions? How did TNA eventually convert into RNA or DNA and is this synthesis prohibitively complex for an early-Earth scenario? If the early Earth only had three bases, how did it eventually come up with a fourth? And, most importantly, how did the relationship among DNA, mRNA, tRNA, and proteins evolve and where does TNA figure in that process?

It seems that much of the origin-of-life research going on now suffers from a kind of myopia where researchers hone in on solving one particular problem without contextualizing their solution. This is like trying to plan a road trip to London, Paris, New York, and Seattle using only photographs of each of the cities. You need to know how each of these cities is connected in order to travel from one to another, but that's a much more difficult task than merely acknowledging that they exist.